Distillation Method for the Purification of Sevoflurane and the Maintenance of Certain Equipment that May be Used in the Distillation Process

ABSTRACT

Processes for preparing commercial quantities of a stable, pharmaceutically acceptable sevoflurane substantially free of impurities are claimed. In another embodiment, a process for removing reactive metal salts from the surface of metallic equipment used in the distillation of sevoflurane and rendering a non-inert metallic surface of the metallic equipment inert.

BACKGROUND OF THE INVENTION

Sevoflurane is produced by several known methods. A commonly used methodinvolves the reaction of formaldehyde (or a formaldehyde equivalent),hydrogen fluoride (HF), and hexafluoroisopropanol (HFIP). U.S. Pat. No.4,250,334 describes a process in which HFIP is added to a mixture of astoichiometric excess of paraformaldehyde and HF plus sufficientsulfuric acid to sequester most of the water formed in the reaction. WO97/25303 describes a process for the production of sevoflurane in whichessentially pure bis(fluoromethyl)ether (BFME) is allowed to react withHFIP and sulfuric acid. U.S. Pat. No. 6,469,219 describes a process inwhich HFIP and a formaldehyde equivalent are allowed to react withexcess HF under distillative or extractive conditions in order toproduce sevoflurane. Other synthetic routes generate a differentimpurity profile, but still require a final distillation in order toproduce a pharmaceutically acceptable form of sevoflurane.

In all of these processes, unreacted HFIP may remain in the productmixture, as well as BFME, methyl hexafluoroisopropyl ether (MHFIP),polyethers containing the HFIP and formaldehyde moieties, and variousother undesired species. These impurities must be removed from the crudesevoflurane product in order to obtain a pharmaceutically acceptableform of the material.

Many of these impurities can be removed by distillation, but it has beendisclosed in U.S. Pat. No. 5,684,211 that crude sevoflurane candecompose or disproportionate under distillative conditions and that theproduct could not be adequately purified as a result of thisdecomposition/disproportionation. For example, dehydrofluorination ofsevoflurane may occur during distillation, leading to fluoromethyl1,1,3,3,3-pentafluoroisopropenyl ether (also known as Compound A) as anew impurity. It is difficult to separate thisdecomposition/disproportionation product from sevoflurane bydistillation because their boiling points are very similar.

This type of decomposition can be prevented by the use of adecomposition suppressive agent in the distillation process. Suppressiveagents known in the art include hydroxides of alkali metals,hydrogenphosphates of alkali metals, phosphates of alkali metals,hydrogencarbonates of alkali metals, borates of alkali metals, sulfitesof alkali metals, alkali metal salts of acetic acid, alkali metal saltsof phthalic acid and boric acid. Potential drawbacks to the use of suchagents, however, include added expense for their use and disposal, aswell as the necessity to completely remove them from the drug product.

Furthermore, although fluoroethers are excellent anesthetic agents, somefluoroethers have been reported to encounter stability problems. Morespecifically, it has been reported (U.S. Pat. No. 5,990,176 and others)that certain fluoroethers, in the presence of one or more Lewis acids,degrade into several by-products including potentially toxic chemicalssuch as HF and/or HFIP. Hydrofluoric acid is toxic by ingestion andinhalation and is highly corrosive to skin and mucous membranes.Therefore, the degradation of fluoroethers to chemicals such as HF is ofgreat concern to the medical community. In fact, quantities of Ultane®brand sevoflurane had to be recalled on two occasions due to potentiallypatient-threatening decomposition caused by exposure to Lewis acids.

The Lewis-acid induced decomposition of sevoflurane can be suppressed bythe addition of certain Lewis-acid inhibitors to the product. Lewis-acidinhibitors include, but are not limited to, water, butylatedhydroxytoluene, methylparaben, propofol, thymol, and propylparaben. Thedrawbacks of using such agents include the added expense and processingtime for their incorporation into the drug product.

Thus, a distillative method is needed for the efficient separation ofsevoflurane from impurities without furtherdecomposition/disproportionation that does not require the use of anytype of suppressive agent in order to achieve a substantially pureproduct. Also, this method should result in a product that does notdecompose over long periods of time, thus eliminating the need for theaddition of sevoflurane decomposition suppression agents.

SUMMARY OF THE INVENTION

The present invention relates to a process for obtaining commercialquantities of substantially pure fluoromethyl1,1,1,3,3,3-hexafluoroisopropyl ether (sevoflurane) withoutdecomposition-causing impurities or decomposition-suppression agents.The process includes providing a crude sevoflurane product, fractionallydistilling the crude sevoflurane product, forming thereby a distillate,and removing substantially pure sevoflurane from the distillate. Thedistillation takes place in equipment having common distillationcomponents. The surfaces of the components that contact sevofluranecontain little or no active metal salts during the time the surfacecontacts the sevoflurane. The resulting substantially pure sevofluraneis stable when stored at room temperature for at least two years. Thereis no requirement for the presence of sevoflurane decompositionsuppression agents during storage, and the substantially puresevoflurane is preferably stored in the absence of such suppressionagents.

A commercial quantity of sevoflurane is an amount more than about 500liters per year, preferably more than about 1000 liters per year, andmost preferably more than about 2000 liters per year.

Substantially pure sevoflurane is sevoflurane which contains less than300 ppm of total impurities, and less than 100 ppm of any individualimpurity. In a preferred embodiment, the “substantially puresevoflurane” contains less than 100 ppm of total impurities, and lessthan 20 ppm of any individual impurity.

Since the sevoflurane of the present invention is substantially free ofimpurities that may lead to decomposition, there is no need for specialcontainers to store the sevoflurane. Therefore, the sevoflurane may bestored in common glass for up to two years and even longer, e.g., three,four, or five years. The preferred glass is Type III glass.

In a preferred embodiment, the distillation is conducted in the absenceof sevoflurane decomposition suppression agents. In another preferredembodiment, sevoflurane decomposition suppression agents are not addedto the substantially pure sevoflurane product subsequent todistillation, e.g., during storage.

Some examples of sevoflurane decomposition suppression agents includehydroxides of alkali metals, hydrogenphosphates of alkali metals,phosphates of alkali metals, hydrogencarbonates of alkali metals,borates of alkali metals, sulfites of alkali metals, alkali metal saltsof acetic acid, alkali metal salts of phthalic acid and boric acid. Someadditional examples of sevoflurane decomposition suppression agentsinclude Lewis-acid inhibitors. Lewis-acid inhibitors include, but arenot limited to, butylated hydroxytoluene, methylparaben, propofol,thymol, and propylparaben.

It should be noted that water is a Lewis-acid inhibitor. Nevertheless,in this embodiment, water may be present in substantially puresevoflurane, usually as a result of previous processing. In a preferredembodiment, however, water is not added during the distillation processor during storage, and the substantially pure sevoflurane product doesnot use ambient or remaining water (nor does it serve) as a Lewis acidinhibitor. The resulting sevoflurane preferably contains less than 100ppm of water, and, in a preferred embodiment, contains less than 70 ppmof water.

The common distillation components include, for example, reboilers,condensers, fractionating columns, transfer lines, and/or storagevessels. The fractionating column preferably contains one or morematerials that aid fractionation. Such materials include, for example,column packing materials, plates, sieve trays, or bubble cap trays. In apreferred embodiment, the column packing materials include PFA. Thecomponents may also include an agitator.

In one embodiment, the surface of at least one component is metallic.The metallic surface may be made of any metal that can be fashioned intodistillation equipment and does not easily form salts. The metalliccomponent should also be stable when in contact with vapor or liquidphases of a crude sevoflurane product or of substantially purifiedsevoflurane. The metallic surfaces include, for example, stainlesssteel, a nickel-copper alloy, alloy 20, copper, nickel, zirconium,titanium, tantalum, chromium, Hastelloys or generic equivalents, orcombinations thereof. For example, Hastelloy C-276 is sold genericallyas Alloy C-276, and Hastelloy C-22 is sold generically as Alloy C-22. Ina preferred embodiment, the metal is stainless steel, and morepreferably the stainless steel is type 316. An example of anickel-copper alloy is Monel or its generic equivalents. Monel 400 isthe preferred Monel.

In another embodiment, the surface of at least one component isnon-metallic. The non-metallic surface may be made of any non-metal thatcan be fashioned into distillation equipment and is stable when incontact with vapor or liquid phases of a crude sevoflurane product or ofsubstantially purified sevoflurane. Some examples of non-metallicsurfaces include plastics, glass, carbon, ceramic, and combinationsthereof. Preferable plastics include fluorinated polymers, polyethylene,polypropylene, or combinations thereof. Preferable fluorinated polymersinclude poly(tetrafluoroethylene) (PTFE), fluorinated ethylene propylene(FEP), perfluoroalkoxy polytetrafluoroethylene (PFA), ethylenetetrafluoroethylene (ETFE), polyvinylidene fluoride (PVF), ethylenechlorotrifluoroethylene (ECTFE), polyvinylidene difluoride (PVDF),polychlorotrifluoroethylene (PCTFE), and combinations thereof. In apreferred embodiment, the surface is PFA.

Another aspect of the invention relates to a process as described above,wherein the crude sevoflurane product is provided by reacting acomposition comprising hexafluoroisopropanol, formaldehyde or itsequivalent, and hydrogen fluoride (HF). The crude sevoflurane productcontains hexafluoroisopropanol, and may contain unreacted startingmaterials, such as HF.

In a preferred embodiment, the amount of HF in the crude sevoflurane isreduced prior to distillation. The amount of HF may be reduced inaccordance with known procedures, such as those described in U.S. Pat.No. 6,469,219, Examples 4-6.

Another aspect of the invention relates to a process for removingreactive metal salts from the surface of metallic equipment used in thedistillation of sevoflurane and rendering a non-inert surface of themetallic equipment inert (i.e., inerting). The surface of the metallicequipment is any surface of the equipment that may come in contact withvapor or liquid phases of a crude sevoflurane product or ofsubstantially purified sevoflurane during the distillation.

Inerting, e.g., passivating, may be accomplished by methods that arewell known in the art. Such methods include, for example, chemical andelectrical treatments. Some examples of chemical treatments includephosphate treatments, for example Parkerizing, as well as oxalate andchromium treatments. Some additional inerting methods includegalvanizing and painting. Anodizing is particularly useful in the caseof aluminum.

The process of the invention includes i) washing the interior surfacesof the metallic equipment one or more times with water. If the pH of thedischarged wash is initially less than 6, washing is carried out untilthe pH of the discharged water is at least 6. Subsequent steps includeii) contacting interior surfaces of the equipment with an aqueoussolution of a passivation agent; iii) removing the aqueous passivationsolution; and iv) rinsing the equipment with water until the pH of thedischarged water is not less than 6. The interior surfaces of theequipment may be contacted with an aqueous solution of a passivationagent by immersing the surfaces in an aqueous solution of a passivationagent or by spraying an aqueous solution of a passivation agent onto thesurfaces.

In this specification, an “interior surface,” “sevoflurane-contactingsurface,” or a “liquid- and gas-contacting surface” is a surface ofdistillation equipment that contacts crude or substantially purifiedsevoflurane in either the gas or liquid phase during the distillationprocess.

A passivation agent is any agent that renders the non-inert surface of ametal, especially stainless steel, inert. Some examples of passivationagents include citric acid, nitric acid, and a mixture of nitric acidand sodium or potassium dichromate. A commercial example of a citricacid passivation agent is the CitriSurf product line supplied by StellarSolutions, 4511 Prime Parkway, McHenry, Ill. 60050. The preferredpassivation agent is nitric acid. Preferred mole percent ratios ofnitric acid and sodium or potassium dichromate in mixtures of the twoinclude 5:95 to 95:5.

In one embodiment, the concentration of the passivation agent ispreferably a minimum of about 1% by weight of the aqueous solution, andmore preferably a minimum of about 10% by weight of the aqueoussolution. In another embodiment, the concentration of the passivationagent is a maximum of about 90% by weight of the aqueous solution, morepreferably a maximum of about 50% by weight of the aqueous solution.

The metallic equipment is preferably in contact with the aqueouspassivation solution for a minimum total time period of about 0.25hours, and more preferably a minimum total time period of about 0.5hour. The metallic equipment is preferably in contact with the aqueoussolution for a maximum total time period of about 48 hours, and morepreferably a maximum total time period of about 24 hours.

The contact temperature when the metallic equipment is in contact withthe aqueous passivation solution is a minimum of about 20° C., morepreferably a minimum of about 35° C., and more preferably about aminimum of about 50° C. The contact temperature when the metallicequipment is in contact with the aqueous passivation solution is amaximum of about 80° C., preferably a maximum of about 70° C., and morepreferably about a maximum of about 60° C. The preferred range is about50° C. to about 60° C.

In another embodiment, the invention relates to a process for obtainingcommercial quantities of substantially pure sevoflurane. The processincludes i) providing a crude sevoflurane product; ii) passivatingliquid- and gas-contacting surfaces of distillation equipment capable ofproviding commercial quantities of sevoflurane; iii) distilling thecrude sevoflurane product in the distillation equipment; and iv)recovering substantially pure sevoflurane. The passivating anddistilling steps are described above in further detail.

DETAILED DESCRIPTION

The present invention provides an improved process for preparingcommercial quantities of stable, pharmaceutically acceptable sevofluranesubstantially free of impurities and without the use of decompositionsuppression agents.

The phrase “substantially pure sevoflurane,” as used herein issevoflurane which contains less than 300 ppm of total impurities, andless than 100 ppm of any individual impurity. In a preferred embodiment,the term “substantially pure sevoflurane” means sevoflurane whichcontains less than 100 ppm of total impurities, and most preferably lessthan 20 ppm of any individual impurity. Total impurities are defined asimpurities not including water.

The term “stable” as used herein means that the substantially puresevoflurane remains substantially pure as herein defined for at leasttwo years from the time of production at ambient temperature, or for atleast three months at 40° C. Stability is achieved without the additionof sevoflurane decomposition suppression agents. Some examples ofsevoflurane decomposition suppression agents include hydroxides ofalkali metals, hydrogenphosphates of alkali metals, phosphates of alkalimetals, hydrogencarbonates of alkali metals, borates of alkali metals,sulfites of alkali metals, alkali metal salts of acetic acid, alkalimetal salts of phthalic acid and boric acid. Some additional examples ofsevoflurane decomposition suppression agents include, but are notlimited to, Lewis-acid inhibitors. Lewis-acid inhibitors include, butare not limited to, butylated hydroxytoluene, methylparaben, propofol,thymol, and propylparaben. It should be noted that water also is aLewis-acid inhibitor. Nevertheless, in this embodiment, water may bepresent, usually as a result of previous processing. In a preferredembodiment, water is not added to any water than may already be presentduring the distillation process.

A commercial quantity of sevoflurane is an amount more than about 500liters per year, preferably more than about 1000 liters per year, andmost preferably more than about 2000 liters per year.

A crude sevoflurane product comprising unacceptably high levels ofimpurities can be purified by distilling the crude sevoflurane productusing process equipment that contains little or no active metal salts.Such surfaces do not contain enough active metal salts to causesignificant decomposition/disproportionation of the product. Purifiedsevoflurane distilled from this type of equipment is stable, without theaddition of sevoflurane decomposition suppression agents, for at leasttwo years when stored at ambient temperature and/or for at least threemonths at 40° C. It should be noted that water may be present as aresult of previous processing, but is not added.

The crude sevoflurane product can be prepared in any manner. Preferablythe crude sevoflurane product is produced by a process comprisingreacting hexafluoroisopropanol (HFIP), formaldehyde, and hydrogenfluoride (HF).

Preferably, the reaction is carried out in a stoichiometric excess ofHF. The reaction temperature is not critical, but the yields aresubstantially improved above 50° C. Preferably, the reaction isconducted under autogenous pressure of 30-40 psig ensuring temperaturesof 45-75° C. The process is described in U.S. Pat. No. 6,469,219, whichis hereby incorporated by reference.

In a preferred embodiment, the amount of HF in the crude sevoflurane isreduced prior to distillation. The amount of HF is reduced in accordancewith known procedures such as those described in U.S. Pat. No.6,469,219, Examples 4-6 to obtain a second crude sevoflurane product.

The term “formaldehyde” as used herein means not only formaldehyde perse, but also any equivalent of formaldehyde. Equivalents of formaldehydeinclude formaldehyde polymers, such as trioxane, and paraformaldehyde.

Fractional distillation is a widely used, well-understood commercialprocess. The equipment used in such a process includes, but is notlimited to, reboilers, condensers, fractionating column, transfer lines,and storage vessels. A fractionating column may include column packingmaterials, plates, sieve trays, and bubble cap trays. The equipment mayfurther comprise agitators, transfer lines, packing and packing supporthardware, nuts and bolts, pipe fittings and components such as tees,elbows, and valves, and instrumentation such as that used for measuringdifferential pressure, absolute pressure, and temperature.

The appropriate selection of materials for construction of surfaces ofthe equipment depends on well-established factors such as temperaturestability, compatibility with chemical compounds, cost, etc. Inparticular, compatibility with sevoflurane and resistance toacidity/basicity should be considered.

Appropriate non-metallic materials for construction of surfaces of theequipment include, but are not limited to, plastics such as fluorinatedpolymers and polyolefins; glass; carbon; ceramics; and combinationsthereof. Examples of fluorinated polymers include, but are not limitedto, poly(tetrafluoroethylene) (PTFE), fluorinated ethylene propylene(FEP), perfluoroalkoxy polytetrafluoroethylene (PFA), ethylenetetrafluoroethylene (ETFE), polyvinylidene fluoride (PVF), ethylenechlorotrifluoroethylene (ECTFE), polyvinylidene difluoride (PVDF),polychlorotrifluoroethylene (PCTFE). Fluorinated polymers sold by DuPontunder the tradename TEFLON® and their generic equivalents areparticularly useful in this invention. Examples of polyolefins include,but are not limited to, polyethylene and polypropylene.

Appropriate metals for the construction of equipment involved in thefractional distillation of sevoflurane include any metal typically usedin making distillation equipment. Metals appropriate for making thedistillation equipment of the invention do not easily form salts.Examples of appropriate metals include, but are not limited to, highergrades of stainless steel (such as 316 stainless steel), nickel-copperalloys, alloy 20, copper, nickel, zirconium, titanium, tantalum,chromium, Hastelloys or generic equivalents, and combinations of thesemetals. The preferred metal is 316 stainless steel. An example of anickel-copper alloy is Monel 400, which is sold generically as Alloy400. Generic equivalents of Hastelloys are also appropriate metals. Forexample, generic equivalents of Hastelloy C-276 and Hastelloy C-22include Alloy C-276 and Alloy C-22, respectively.

The distillation takes place in equipment having components withsurfaces that contact sevoflurane, and the surfaces contain little or noactive metal salts. The surfaces include all surfaces that come incontact with vapor or liquid phases of a crude sevoflurane product or ofsubstantially purified sevoflurane.

In one embodiment, the equipment can be entirely made of thenon-metallic and metallic materials containing little or no active metalsalts. In another embodiment, only the portion of the equipment thatcontacts sevoflurane during distillation may be coated with thenon-metallic and metallic materials containing little or no active metalsalts.

Surfaces of a component may be made of a non-metallic material, and thesurfaces of another component may be made of a metallic material, Forexample, the reboiler may be coated with 316 stainless steel, and thecondenser may be made entirely of glass.

In a preferred embodiment, a non-metallic material is used as an inertcoating over metallic components. For example, PFA may be used to coatthe packing material used in the column.

As mentioned above, the surface of the metal components must containlittle or no active metal salts that may react with sevoflurane toproduce impurities. Confirmation that the surfaces of the equipmentcontain little or no active metal salts may be accomplished by varioustechniques. A preferred method is to add previously analyzed sevofluraneto the distillation system and perform a standard distillation. Thedistillation may, for example, be conducted using about 300 kgsevoflurane per cubic meter of equipment volume over a period of 24hours. The resultant distillate and residual pot contents are analyzedfor impurities. If there is no increase in the amount of impurities inthe sevoflurane, the distillation system is confirmed to be sufficientlyfree of active metal salts, and is ready for use.

When metallic components are used in the distillation process equipment,constant care must be maintained in order to avoid the generation ofreactive metal salts which may cause the decomposition of sevofluraneeither during the distillation process or upon storage for long periodsof time. Reactive metal salts are any salts which contribute to thegeneration of impurities in sevoflurane. Common reactive metal saltsinclude halides, nitrates, and sulfates of the metals used. Examples ofreactive metal salts include iron chloride(s), iron fluoride(s), ironnitrate(s), iron sulfate(s), copper chloride(s), copper fluoride(s),copper nitrate(s), copper sulfate(s), nickel chloride(s), nickelfluoride(s), nickel nitrate(s), and nickel sulfate(s).

The distillation system must be routinely monitored for indications ofunexpected reactive metal salt formation. Monitoring techniques includeperiodic visual inspection of metallic components for signs of corrosionand regular monitoring of final product distillate for the presence ofelevated quantities of impurities as described above.

If unacceptable quantities of reactive metal salts are detected in thedistillation equipment or there is reason to believe there are salts onthe surface of the equipment, the reactive metal salts must be removedand the surface of the metal components must be protected before anyfurther processing is attempted. One potential method for accomplishingthis type of purification, particularly for components made fromstainless steel, is called passivation. This process involves thetreatment of the surfaces of metallic equipment with an aqueous solutionof a passivation agent that removes metal salts while rendering anon-inert metallic surface of the metallic equipment inert. Examples ofsuitable passivation agents include citric acid, nitric acid, andmixtures of nitric acid and sodium dichromate. The preferred passivationagent is nitric acid.

In a typical cleaning/recovery procedure, the equipment first is washedthoroughly with water, although this step is optional. If the pH of thedischarged wash is initially less than 6, washing should be carried outuntil the pH of the discharged water is at least 6. Thesevoflurane-contacting surfaces of the equipment are then placed incontact for a period of time with a passivation solution. After thepassivation solution is removed, the equipment is rinsed repeatedly withwater until all of the passivation solution and dissolved metal saltshave been removed from the system. After it has been confirmed that allof the passivation solution has been removed, the equipment is dried byconventional methods.

The concentration of the passivation agent in the aqueous solution iseffective at a minimum of about 1% by weight of the aqueous solution,and more preferably about 10% by weight of the aqueous solution. Themaximum concentration of the passivation agent in the aqueous solutionis about 90% by weight of the aqueous solution, and more preferablyabout 50% by weight of the aqueous solution. The contact time for thetreatment of the metallic components with the aqueous solution willdepend on several factors, including the concentration of thepassivation agent and the amount of metal-salt contamination.

Sufficient contact time is determined retrospectively by placing theequipment back into service and monitoring the next sevofluranedistillate for the presence of unacceptably large quantities ofimpurities, as discussed previously. The normal time for contact of theequipment with the passivation solution is a minimum of about a quarterof an hour, and more preferably about 30 minutes. The maximum amount oftime for contact of the equipment with the passivation solution is about48 hours, preferably about 24 hours.

The contact temperature for the treatment of the metallic componentswith the passivation solution will depend upon several factors includingthe concentration of the passivation agent, and the amount of thesuspected metal salt contamination. Sufficient contact temperature isdetermined retrospectively by placing the equipment back into serviceand monitoring the next sevoflurane distillate for the presence ofunacceptably large quantities of impurities, as discussed previously.The contact temperature when the metallic equipment is in contact withthe aqueous passivation solution is a minimum of about 20° C., morepreferably a minimum of about 35° C., and more preferably about aminimum of about 50° C. The contact temperature at when the metallicequipment is in contact with the aqueous passivation solution is amaximum of about 80° C., preferably a maximum of about 70° C., and morepreferably about a maximum of about 60° C. The preferred range is about50° C. to about 60° C.

When metallic equipment used in the distillation of sevoflurane has beencleaned according to method described above, the metallic equipment maybe reused to make substantially pure sevoflurane that exhibits stabilityat room temperature for at least two years without the addition ofsevoflurane decomposition suppression agents.

In another embodiment, the invention relates to a process for obtainingcommercial quantities of substantially pure sevoflurane. The processcomprises:

i) providing a crude sevoflurane product;

ii) passivating liquid- and gas-contacting surfaces of distillationequipment capable of providing commercial quantities of sevoflurane;

iii) distilling the crude sevoflurane product in the distillationequipment; and recovering substantially pure sevoflurane.

The acts of providing a crude sevoflurane product, passivating liquid-and gas-contacting surfaces of distillation equipment capable ofproviding commercial quantities of sevoflurane, distilling the crudesevoflurane product in the distillation equipment, and storing thesubstantially pure sevoflurane are as described above. Preferably,sevoflurane decomposition suppression agents are not added to thesevoflurane during the distillation. The substantially pure sevofluranemay be stored up to two years in glass containers, preferably Type IIIglass containers, with or without the presence of sevofluranedecomposition suppression agents.

1-37. (canceled)
 38. A process for obtaining commercial quantities ofsubstantially pure sevoflurane comprising: i) providing a crudesevoflurane product; ii) passivating liquid- and gas-contacting surfacesof distillation equipment capable of providing commercial quantities ofsevoflurane; iii) distilling the crude sevoflurane product in thedistillation equipment; and iv) recovering substantially puresevoflurane.
 39. The process according to claim 38, wherein sevofluranedecomposition suppression agents are not added to the sevoflurane duringthe distillation.
 40. The process according to claim 38, furthercomposing storing the substantially pure sevoflurane up to two years.41. The process according to claim 39, wherein the substantially puresevoflurane product is stored in glass containers.
 42. The processaccording to claim 41, wherein the glass containers are made of Type IIIglass.
 43. The process according to claim 41, wherein sevofluranedecomposition suppression agents are not added to sevoflurane duringstorage.
 44. The process according to claim 38, wherein the distillationequipment is metallic.
 45. The process according to claim 44, whereinstep ii) comprises: a) washing the metallic equipment one or more timeswith water, and if the pH of the discharged wash is initially less than6, continuing washing until the pH of the discharged wash is at least 6;b) contacting the surfaces of the equipment that are to be treated withan aqueous solution of a passivation agent; c) removing the aqueouspassivation agent; and d) rinsing the equipment with water, and if thepH of the discharged wash is initially less than 6, continuing washinguntil the pH of the discharged water is at least
 6. 46. A processaccording to claim 38, wherein the passivation agent is citric acid,nitric acid, and a mixture of nitric acid and sodium dichromate.
 47. Aprocess according to claim 38, wherein the passivation agent is nitricacid.
 48. A process for removing reactive metal salts from thesevoflurane-contacting surfaces of metallic equipment used in thedistillation of sevoflurane and rendering the surfaces inert, theprocess comprising: i) washing the metallic equipment one or more timeswith wafer, and if the pH of the discharged wash is initially less than6, continuing washing until the pH of the discharged wash is at least 6;ii) contacting the surfaces of the equipment that are to be treated withan aqueous solution of a passivation agent; iii) removing the aqueouspassivation agent; and iv) rinsing the equipment with water, and if thepH of the discharged wash is initially less than 6, continuing washinguntil the pH of the discharged water is at least
 6. 49. A processaccording to claim 48, wherein the concentration of the passivationagent is a minimum of about 1% by weight of the aqueous passivationsolution.
 50. A process according to claim 48, wherein the concentrationof the passivation agent is a minimum of about 10% by weight of theaqueous passivation solution.
 51. A process according to claim 48,wherein the concentration of the passivation agent is a maximum of about90% by weight of the aqueous passivation solution.
 52. A processaccording to claim 48, wherein the concentration of the passivationagent is a maximum of about 50% by weight of the aqueous passivationsolution.
 53. A process according to claim 48, wherein the metallicequipment is in contact with the aqueous passivation solution for aminimum total time period of about 0.25 hours.
 54. A process accordingto claim 48, wherein the metallic equipment is in contact with theaqueous passivation solution for a minimum total time period of about0.30 hours.
 55. A process according to claim 48, wherein the metallicequipment is in contact with the aqueous passivation solution for amaximum total time period of about 48 hours.
 56. A process according toclaim 48, wherein the metallic equipment is in contact with the aqueouspassivation solution for a maximum total time period of about 24 hours.57. A process according to claim 48, wherein the passivation agent iscitric acid, nitric acid, or mixtures of nitric acid and sodiumdichromate.
 58. A process according to claim 57, wherein the passivationagent is nitric acid.
 59. A process according to claim 48, wherein themetallic equipment comprises stainless steel.
 60. A process according toclaim 48, wherein the contact temperature when the metallic equipment isin contact with the aqueous passivation solution is a minimum of about20° C.
 61. A process according to claim 48, wherein the contacttemperature when the metallic equipment is in contact with the aqueouspassivation solution is a minimum of about 35° C.
 62. A processaccording to claim 48, wherein the contact temperature when the metallicequipment is in contact with the aqueous passivation solution is aminimum of about 50° C.
 63. A process according to claim 48, wherein thecontact temperature when the metallic equipment is in contact with theaqueous passivation solution is a maximum of about 60° C.
 64. A processaccording to claim 48, wherein the contact temperature when the metallicequipment is in contact with the aqueous passivation solution is amaximum of about 70° C.
 65. A process according to claim 48, wherein thecontact temperature when the metallic equipment Is in contact with theaqueous passivation solution is a maximum of about 80° C.